title: Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation.
abstract: OBJECTIVE
  It has been suggested that nitric oxide (NO) is involved in the regulation of myocardial function in a variety of diseases such as dilated cardiomyopathy, myocarditis, heart transplant rejection, and septic shock. However, the underlying mechanism of NO mediated reduction of cardiac contractility has not been clearly established so far. Therefore, we studied the effects of authentic NO on left ventricular function and myocardial energy status in the isolated heart.
  
  
  METHODS
  In 43 isolated perfused guinea pig hearts quantitative and kinetic changes in coronary flow (CF), left ventricular developed pressure (LVDP), the cardiac release of adenosine, lactate, cyclic GMP, and norepinephrine were measured during infusion of authentic NO. In parallel, myocardial phosphocreatine (PCr), ATP and the free energy change of ATP-hydrolysis (delta GATP) were measured using 31P nuclear magnetic resonance spectroscopy.
  
  
  RESULTS
  At low concentrations (0.01 to 1.0 mumol/L) NO increased CF only; at higher concentrations (1 to 100 mumols/L) CF remained elevated and LVDP was significantly reduced. Onset and offset of changes in LVDP occurred always within 2 to 5 s after start and cessation of NO infusion. Contractile dysfunction was significantly correlated to a pronounced increase in adenosine formation (> 70-fold), a significant decrease in myocardial PCr (-78%), ATP (-25%) and a decrease in delta G(ATP) from -61.76 kJ/mol to -50.75 kJ/mol. This was paralleled by a significant decrease in myocardial oxygen consumption (-65%) and a tenfold increase in lactate production. Coronary vasodilation (NO: 0.001 to 1.0 mumol/L) significantly correlated with the increase in cGMP release, whereas at negative inotropic concentrations (NO: 10 to 100 mumols/L) a clear quantitative and kinetic dissociation between NO-induced changes in cGMP and LVDP was observed. Contractile dysfunction was not related to cardiac release of norepinephrine.
  
  
  CONCLUSIONS
  In the isolated heart NO can potently depress myocardial energy generation thus being an effective modulator of cardiac contractility. This effect of NO may be of pathophysiological significance in cardiac muscle disorders in vivo.
authors.affiliation: Department of Medicine, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kelm
authors.forename: S
authors.initials: S
authors.lastname: Schäfer
authors.forename: R
authors.initials: R
authors.lastname: Dahmann
authors.forename: B
authors.initials: B
authors.lastname: Dolu
authors.forename: S
authors.initials: S
authors.lastname: Perings
authors.forename: U K
authors.initials: UK
authors.lastname: Decking
authors.forename: J
authors.initials: J
authors.lastname: Schrader
authors.forename: B E
authors.initials: BE
authors.lastname: Strauer
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D006168:Guinea Pigs; D006868:Hydrolysis; D019344:Lactic Acid / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D010725:Phosphocreatine; D009569:Nitric Oxide; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D006152:Cyclic GMP; D000241:Adenosine; D009638:Norepinephrine